The proposed program project, a restructuring both of subject matter and personnel of a program started in 1961, would be devoted to structure-function and genetic studies of Fs. VIII and IX to be carried out in the Division of Health Sciences of the University of North Carolina. An administrative core and 4 sub-projects are proposed. The genetics sub-project involving Drs. Graham, Barrow, Reisner, Elston, Blatt and Sher will carry out cytogenetic, linkage, population genetic and immunogenetic studies of Fs. VIII and IX. They hope to localize the hemophilia genes on chromosomes, establish linkage groups and define certain genetic parameters of the hemophilia genes as they presently exist (prevalence, fitness, mutation rate); they also propose work on carrier detection. The sub-project on F. IX will involve Drs. Roberts, Lundblad, Dombrose, Reisner, Chung and Goldsmith. They will attempt to define the structural features of F. IX responsible for its biological activity, by studying the structural and functional relations of normal and abnormal F. IX molecules. These will be examined with respect to calcium binding, phospholipid surface binding, ability to form F. activator, and the results will be correlated with peptide sequences and immunologic determinants. The sub-project of Drs. Wagner and Cooper will be a detailed study of the F. VIII complex and its components as isolated from highly purified preparations. They intend to characterize by a variety of biochemical and immunologic procedures the low and high molecular weight VIII:C components which can be dissociated with calcium, thrombin, and DTT. The knowledge obtained will be applied to the study of variants of hemophilia A and von Willebrand's disease. Dr. Kingdon will attempt to modify Fs. VIII and IX chemically such that: 1) coagulant function is retained, 2) circulatory half-life is prolonged and 3) immunogenicity is avoided.